The long-term objective of this Project is to reduce the morbidity and mortality from prostate cancer by preventing its development, promotion, or progression by interrupting polyamine synthesis. The major hypothesis to be tested is to determine whether alpha-difluoromethylornithine (DFMO), an enzyme activated irreversible inhibitor of ornithine decarboxylase (the rate-limiting step of polyamine syntheses), can suppress tissue polyamine content and progression-related genes in prostate tissue of individuals at high genetic risk for prostate cancer. Two major specific aims will be addressed: (1) to conduct a randomized, placebo-controlled, double-blind phase IIB trial of DFMO in bothers and fir-cousin males of probands with familial history of early onset prostate cancer (identified by Project I). (2) to carefully assess the side effects of DFMO in this population and to compare them to the biological effects on the prostate gland. Surrogate endpoint biomarkers (Project II) will be measured in the prostate gland obtained by sextant biopsy at baseline and post-treatment (after one year). Baseline and post-treatment free and total PSA density will also be measured. Appropriate correlations with modulation of surrogate endpoint biomarkers will be assessed. The long-term goal of the Project is to determine if suppression of prostate polyamine contents is an effective strategy for prevention of prostate cancer in human males.